This collaborative project, "Protease Inhibitors, Atherogenic Lipoproteins and Premature Atherosclerosis" comprises three proposals. Taken together, the studies will investigate potential atherosclerotic effects of protease inhibitors and assess their relationship to subclinical cardiovascular disease. The effects of HIV infection and associated antiretroviral therapy on plasma lipoprotein subclasses and pro-oxidant stress will be assessed under diverse clinical conditions to determine if HIV and its therapy, in particular protease inhibitors, induce a proatherogenic milieu. Mechanisms whereby protease inhibitors may promote atherosclerosis in humans will be explored in a series of clinical studies: utilizing antiretroviral regimens with and without protease inhibitors, treating uninfected volunteers and using thalidomide to reduce the effects of TNFalpha in patients with advanced HIV infection. In vitro cell culture experiments and animal models will be used to test the hypothesis that HIV protease inhibitors interfere with normal function of certain low density lipoprotein receptor family members, and that dysregulation of receptor function has a deleterious effect and may accelerate atherosclerosis. The presence of subclinical cardiovascular disease, and its relationship to the atherogenic lipoprotein phenotype and pro- oxidant stress levels will be assessed using several markers of atherosclerosis including flow-mediated brachial reactivity, carotid intima-media thickness, coronary calcification and electron beam computed tomographic angiography. The impact of intervention with gemfibrozil will also be examined. The three projects are interwoven, both through an umbrella hypothesis and shared experimental materials. Subjects recruited for each clinical project will provide samples or measures to be used in other projects' assays or analyses. Results from in vitro studies and the animal model will affect design of clinical studies. Shared resources include an administrative/statistical support group, NMR spectroscopic lipid laboratory and pro-oxidant stress laboratory. The investigators will conduct ongoing discussions of study procedures and results, both to ensure smooth interaction of the research groups and to stimulate new analyses and initiatives.